Obesity, a phenotype having high heritability in humans, constitutes the major risk factor predisposing an individual to non-insulin-dependent diabetes mellitus (NIDDM). However, most obese humans do not develop NIDDM, indicating that diabetogenesis entails a complex interaction between obesity genes and other predisposing susceptibility traits. The possible nature of some of these background modifiers is being elucidated by analysis of genetically obese mice. Mutations at loci on six different mouse chromosomes produce obesity, but development of insulin-resistant diabetes requires an interaction between the obesity mutation and other factors in the genetic background. Analysis of the interaction between three distinct obesity genes expressed on the same genetic background has shown that virilization of hepatic sex steroid metabolism mediated via aberrant shifts in sex steroid sulfotransferase activities is a prerequisite for diabetogenesis. The analogies between the development of a hyperandrogenized tissue state in obese mice with obesity-diabetes syndromes in humans are discussed.